Competitive nuclear export of cyclin D1 and Hic-5 regulates anchorage dependence of cell growth and survival.
Anchorage dependence of cell growth and survival is a critical trait that distinguishes nontransformed cells from transformed cells. We demonstrate that anchorage dependence is determined by anchorage-dependent nuclear retention of cyclin D1, which is regulated by the focal adhesion protein, Hic-5, whose CRM1-dependent nuclear export counteracts that of cyclin D1. An adaptor protein, PINCH, interacts with cyclin D1 and Hic-5 and potentially serves as an interface for the competition between cyclin D1 and Hic-5 for CRM1. In nonadherent cells, the nuclear export of Hic-5, which is redox-sensitive, was interrupted due to elevated production of reactive oxygen species, and cyclin D1 was exported from the nucleus. When an Hic-5 mutant that was continuously exported in a reactive oxygen species-insensitive manner was introduced into the cells, cyclin D1 was retained in the nucleus under nonadherent conditions, and a significant population of cells escaped from growth arrest or apoptosis. Interestingly, activated ras achieved predominant cyclin D1 nuclear localization and thus, growth in nonadherent cells. We report a failsafe system for anchorage dependence of cell growth and survival.
Mori
Kazunori
K
Department of Microbiology, Showa University School of Pharmaceutical Sciences, Tokyo, Japan.
Hirao
Etsuko
E
Toya
Yosuke
Y
Oshima
Yukiko
Y
Ishikawa
Fumihiro
F
Nose
Kiyoshi
K
Shibanuma
Motoko
M
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010084:Oxidation-Reduction; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C490232:Lims1 protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C090090:Tgfb1i1 protein, mouse; D019938:Cyclin D1; D018631:ras Proteins